RESUMO
Leucoproliferative Theileria parasites possess the unique capability to transform their bovine host cell, resulting in tumour-like characteristics like uncontrolled proliferation. The molecular mechanisms underlying this parasite-dependent process are only poorly understood. In the current study, bioinformatic analysis of the Theileria annulata surface protein (TaSP) from different T. annulata isolates identified a conserved CDK1 phosphorylation motif T131 PTK within the extracellular, polymorphic domain of TaSP. Phosphorylation assays with radioactively labelled ATP as well as ELISA-based experiments using a phospho-threonine-proline (pThr-Pro) antibody revealed, that CDK1-cyclin B specifically phosphorylates T131 , identifying TaSP as a substrate in vitro. Confocal microscopy and proximity ligation assays suggest an interaction between CDK1 and TaSP in T. annulata-infected cells. Further studies demonstrated a nearly complete co-localization of the pThr-Pro signal and TaSP only in cells in interphase, pointing towards a cell cycle-dependent event. Immunostainings of isolated, non-permeabilized schizonts confirmed the presence of the pThr-Pro epitope on the schizont's surface. Lambda phosphatase treatment abolished the pThr-Pro signal of the schizont, which was reconstituted by the addition of CDK1-cyclin B. Treatment of T. annulata-infected cells with the CDK1 inhibitor purvalanol A resulted in morphological changes characterized by tubulin-rich cell protrusions and an extension of the schizont, and a dose-dependent reduction of BrdU incorporation and Ki67 staining of T. annulata-infected cells, demonstrating a clear impact on the Theileria-dependent proliferation of the bovine host cell. Our data reveal the parasite surface protein TaSP as a target for the host cell kinase CDK1, a major player during cell division. Targeting the uncontrolled proliferation of Theileria-infected cells is a novel and reasonable approach to limit parasite load in order to facilitate a successful cellular immune response against the parasite.
Assuntos
Proteína Quinase CDC2/metabolismo , Doenças dos Bovinos/prevenção & controle , Proteínas de Protozoários/metabolismo , Theileria annulata/imunologia , Theileriose/prevenção & controle , Motivos de Aminoácidos , Animais , Proteína Quinase CDC2/antagonistas & inibidores , Bovinos , Doenças dos Bovinos/parasitologia , Proliferação de Células , Ensaio de Imunoadsorção Enzimática/veterinária , Fosforilação , Purinas/farmacologia , Esquizontes , Theileria annulata/metabolismo , Theileriose/parasitologiaRESUMO
The intracellular protozoan parasite Theileria annulata causes a severe, and often fatal, disease of pure and cross-bred cattle in tropical and subtropical countries. The present review refers to the importance of innate immunity as far as it is known to date in this infectious disease. Specifically, macrophages and the mediators produced by these cells are outlined. In addition, the latest findings concerning cattle breed differences in susceptibility to T. annulata infection in relation to macrophage activation are discussed.
Assuntos
Imunidade Inata , Ativação de Macrófagos , Theileria annulata , Theileriose/imunologia , Animais , Bovinos , Proliferação de Células , Predisposição Genética para Doença , Interações Hospedeiro-Parasita , Fatores Imunológicos/metabolismo , Ativação de Macrófagos/genética , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/parasitologia , Modelos Imunológicos , Óxido Nítrico/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Transdução de Sinais , Especificidade da Espécie , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/parasitologia , Theileriose/genética , Theileriose/fisiopatologia , Theileriose/prevenção & controleRESUMO
In this study potential molecular markers for identification of attenuation in a Theileria lestoquardi-infected cell line to be used in vaccination trials were identified. Two markers associated with attenuation in Theileria annulata vaccine strains were analyzed (metalloproteinase activity and TNF? mRNA expression). The result showed a decreased activity of MMP 9 and decreased mRNA expression of TNF? with increasing passage number. Suppression subtractive hybridization was used to identify potential new markers of attenuation. Random screening revealed nine differentially expressed genes, one from the parasite and eight from the host. Quantitative real time-PCR confirmed mRNA expression of the parasite vacuolar H+ATPase to be downregulated at higher passages.
Assuntos
Regulação da Expressão Gênica , Metaloproteinase 9 da Matriz/metabolismo , Proteínas de Protozoários/genética , Theileria/crescimento & desenvolvimento , Theileria/patogenicidade , Fator de Necrose Tumoral alfa/metabolismo , ATPases Vacuolares Próton-Translocadoras/metabolismo , Animais , Bovinos , Linhagem Celular , Interações Hospedeiro-Patógeno , Metaloproteinase 9 da Matriz/genética , Proteínas de Protozoários/metabolismo , Inoculações Seriadas , Ovinos , Fator de Necrose Tumoral alfa/genética , ATPases Vacuolares Próton-Translocadoras/genéticaRESUMO
Cattle which survive an infection with Theileria annulata become effectively immune to challenge with the same parasite strain, and are thought to be protected against a heterologous strain of the parasite. T-cells play a crucial role in both induction and maintenance of immunity to T. annulata. The generation of cytotoxic T lymphocytes (CTL) is closely related to the control of the infection - macroschizont-infected cells are killed in an MHC class I restricted manner. Any strain-specificity induced by immunisation is likely to be manifested by CTL. Besides CTLs, CD4+ T-cells also play an important role in protective immunity to T. annulata infection.
Assuntos
Vacinas Protozoárias/imunologia , Linfócitos T Citotóxicos/imunologia , Theileria annulata/imunologia , Theileriose/imunologia , Animais , Bovinos , Citotoxicidade Imunológica , Ativação Linfocitária , Vacinas Protozoárias/administração & dosagem , Theileriose/parasitologia , Theileriose/prevenção & controle , VacinaçãoRESUMO
Clone 5 has been described as an immunogenic protein and was used to establish an ELISA for malignant theileriosis. Molecular characterization of the gene product revealed alternative splicing at the single intron resulting in two mRNA transcripts, translating into a long and a short protein form. Homologues of clone 5 exist in Theileria annulata and T. parva according to the available annotated GenBank sequences, showing however only the long protein forms in these parasites (GenBank accession numbers CAI73679, EAN33624). The present study aimed to determine whether two splice variants of homologues of clone 5 occur in T. annulata and T. parva.
Assuntos
Genes de Protozoários , Splicing de RNA , RNA Mensageiro/genética , Theileria/genética , Animais , Sequência de Bases , Primers do DNA , Ensaio de Imunoadsorção Enzimática , Dados de Sequência Molecular , Homologia de Sequência de Aminoácidos , Especificidade da Espécie , Theileria/classificaçãoRESUMO
The pulmonary collectin surfactant protein (SP)-A has a pivotal role in anti-inflammatory modulation of lung immunity. The mechanisms underlying SP-A-mediated inhibition of LPS-induced NF-kappaB activation in vivo and in vitro are only partially understood. We previously demonstrated that SP-A stabilizes IkappaB-alpha, the primary regulator of NF-kappaB, in alveolar macrophages (AM) both constitutively and in the presence of LPS. In this study, we show that in AM and PBMC from IkappaB-alpha knockout/IkappaB-beta knockin mice, SP-A fails to inhibit LPS-induced TNF-alpha production and p65 nuclear translocation, confirming a critical role for IkappaB-alpha in SP-A-mediated LPS inhibition. We identify atypical (a) protein kinase C (PKC) zeta as a pivotal upstream regulator of SP-A-mediated IkappaB-alpha/NF-kappaB pathway modulation deduced from blocking experiments and confirmed by using AM from PKCzeta-/- mice. SP-A transiently triggers aPKCThr(410/403) phosphorylation, aPKC kinase activity, and translocation in primary rat AM. Coimmunoprecipitation experiments reveal that SP-A induces aPKC/p65 binding under constitutive conditions. Together the data indicate that anti-inflammatory macrophage activation via IkappaB-alpha by SP-A critically depends on PKCzeta activity, and thus attribute a novel, stimulus-specific signaling function to PKCzeta in SP-A-modulated pulmonary immune response.
Assuntos
Quinase I-kappa B/metabolismo , Proteína Quinase C/metabolismo , Proteína A Associada a Surfactante Pulmonar/uso terapêutico , Transporte Ativo do Núcleo Celular , Animais , Membrana Celular/enzimologia , Células Cultivadas , Ativação Enzimática , Quinase I-kappa B/genética , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Mutação/genética , NF-kappa B/metabolismo , Fosfotreonina/metabolismo , Ligação Proteica , Proteína Quinase C/deficiência , Proteína Quinase C/genética , Ratos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Research on malignant theileriosis is affected by the limited access to biological materials required for studies aiming at controlling the disease through the establishment of diagnostic tools and vaccines. The main aims of this work were to isolate, establish, and characterize a Theileria lestoquardi-infected cell culture (line) as a source of biological material and to generate a schizont cDNA library for further studies aiming at the identification of antigenic proteins. The T. lestoquardi isolate used originated from a sheep showing typical signs of malignant theileriosis in Atbara town in northern Sudan, and was maintained as an infected cell culture. A high-quality representative schizont cDNA library was established by isolating and purifying the schizonts using a nocodazole/aerolysin protocol followed by Percoll gradient ultracentrifugation. As a parameter to assess the quality of the schizont library, a provisional estimation of the percentage of recombinant phage clones originating from T. lestoquardi (Atbara) was undertaken. Ten clones with inserts ranging in size between 600 and 1200 bp were selected randomly, sequenced, and subjected to BLAST similarity searches. As 6 of the 10 sequenced clones showed similarities to T. parva, T. annulata, and other apicomplexan genes, it was concluded that the majority of the library phage clones originated from the parasite and not from host cell transcripts. The cDNA library will be used for screening of antigenic proteins using sera from infected sheep.
Assuntos
Antígenos de Protozoários/análise , Biblioteca Gênica , Doenças dos Ovinos/parasitologia , Theileria/isolamento & purificação , Theileriose/parasitologia , Animais , Antígenos de Protozoários/genética , Antígenos de Protozoários/imunologia , Sequência de Bases , Linhagem Celular , Reações Cruzadas , Técnica Indireta de Fluorescência para Anticorpo/veterinária , Dados de Sequência Molecular , Vacinas Protozoárias , Esquizontes/imunologia , Ovinos , Doenças dos Ovinos/diagnóstico , Doenças dos Ovinos/prevenção & controle , Sudão , Theileria/genética , Theileria/imunologia , Theileria/patogenicidade , Theileriose/diagnóstico , Theileriose/prevenção & controleRESUMO
Theileria and Babesia are tick-transmitted protozoa that cause great economical losses in livestock. Recently, interest has risen in sheep-infecting piroplasms and a number of previously unidentified pathogens were described, particularly in China. To address the phylogenetic relationship of Theileria and Babesia species infecting sheep, the complete sequences of the 18 S small subunit ribosomal RNA genes of a panel of piroplasm isolates, including T. lestoquardi, T. ovis, T. separata, B. ovis, B. motasi, B. crassa, and several novel species, were compared. The classification based on the established phylogenetic tree corresponded with traditional systematics and revealed that sheep/goat piroplasm species are of a polyphyletic origin. In addition, these studies revealed the existence of at least two novel sheep/goat piroplasm species, designated Theileria sp. (China 1) and Theileria sp. (China 2).
Assuntos
Babesia/classificação , Doenças das Cabras/parasitologia , Filogenia , Doenças dos Ovinos/parasitologia , Theileria/classificação , Animais , Babesia/genética , China , Cabras , RNA Ribossômico 18S/genética , Ovinos , Especificidade da Espécie , Theileria/genéticaRESUMO
A Theileria annulata protein (TaD) exhibiting an N-terminal signal sequence for endoplasmic reticulum membrane translocation and a conserved cysteine-rich region was isolated by screening the mRNA of a T. annulata-infected bovine lymphoblastoid cell line with degenerated primers directed against T. annulata-targeting sequences. The TaD-coding sequence was found to be most closely related to the genomic DNA sequence of T. parva (TIGR database, 72%) and the amino acid sequence of Plasmodium falciparum (41%), P. yoelii yoelii (38%) and Cryptosporidium parvum (36%). The TaD mRNA is expressed within the sporozoite, schizont and merozoite stages of the parasite, implying that it is constitutively transcribed throughout the parasite's life cycle. Allelic variants were found between isolates originating from different geographical regions, however not affecting conserved cysteines. The open reading frame encoded a protein of 19.5 kDa and non-reducing SDS-PAGE analysis demonstrated a homodimeric protein. Using confocal microscopy, the protein was found to be both located in the parasite cytoplasm and to colocalize with a transmembrane protein of the schizonts within infected cells.
Assuntos
Regulação da Expressão Gênica , Sinais Direcionadores de Proteínas/genética , Proteínas de Protozoários/genética , Frações Subcelulares/metabolismo , Theileria annulata/metabolismo , Sequência de Aminoácidos , Animais , Bovinos , Linhagem Celular , Sequência Consenso , Dados de Sequência Molecular , Polimorfismo de Fragmento de Restrição , Proteínas de Protozoários/química , Proteínas de Protozoários/metabolismo , Theileria annulata/genética , Theileria annulata/crescimento & desenvolvimentoRESUMO
A three-dimensional culture system for primary human mononuclear cells was developed, which reproducibly resulted in the formation of multicellular heterospheroids. Immunohistological characterization demonstrated not only the three-dimensional tissue-like aggregation of primary monocytes, B cells and T cells, but also the presence of macrophages and proliferating cells, indicating that a differentiation of monocytes to macrophages and an activation of cells were induced. Because of the phenotypical resemblance to granulomas the influence of an in vitro infection with mycobacteria on spheroid formation and morphology was analyzed. In comparison to control incubations, the formation of multinucleated giant cells and necrotic areas containing large numbers of mycobacteria could be observed, which resembled histological hallmarks of in situ tuberculoid granulomas. These characteristics have not been described for in vitro models of granuloma formation before and thus this new culture technique may prove to be a useful tool for analyzing aspects relevant to immunopathological processes in chronically inflamed tissues.
Assuntos
Leucócitos Mononucleares/citologia , Esferoides Celulares/citologia , Diferenciação Celular/fisiologia , Divisão Celular/fisiologia , Células Cultivadas , Técnicas de Cocultura , Técnicas de Cultura , Granuloma/microbiologia , Granuloma/patologia , Humanos , Imunofenotipagem , Leucócitos Mononucleares/imunologia , Mycobacterium bovis/citologia , Mycobacterium tuberculosis/citologia , Esferoides Celulares/imunologiaRESUMO
Wegener's granulomatosis (WG) is an autoimmune disease characterized by granulomatous lesions and a necrotizing vasculitis. Th1-type-cells lacking CD28 are expanded independent of age and immunosuppressive therapy in WG. To address their migratory properties of CD4(+)CD28(-) T-cells we studied the expression of the inducible inflammatory Th1-type chemokine receptor CCR5 in localized WG and generalized WG. Expansion of CD4(+)CD28(-) T-cells was more prominent in generalized WG compared to localized WG. In localized WG a larger fraction of CD4(+)CD28(-) T-cells displayed CCR5 expression compared to generalized WG. CCR5 expression was also higher in granulomatous lesions in localized WG. Higher levels of CCR5 expression on CD4(+)CD28(-) T-cells in localized WG may favor stronger CCR5-mediated recruitment of this T-cell subset into granulomatous lesions in localized WG. Expansion of Th-1-type CD4(+)CD28(-)CCR5(+) effector memory T-cells might contribute to disease progression and autoreactivity, either directly, by maintaining the inflammatory response, or as a result of bystander activation.
Assuntos
Linfócitos T CD4-Positivos/metabolismo , Granulomatose com Poliangiite/metabolismo , Receptores CCR5/biossíntese , Antígenos CD28 , Granulomatose com Poliangiite/genética , Humanos , Receptores CCR5/genéticaRESUMO
Polymorphisms in the tumor necrosis factor and interleukin-10 genes, linked to cytokine inducibility, may influence the inflammatory response to infection. We studied the biallelic interleukin-10-1082 promoter, the tumor necrosis factor-alpha-308 promoter, and the lymphotoxin-alpha polymorphisms with regard to the development of septic shock in pneumococcal infection. Sixty-nine patients with pneumococcal disease (61 patients with community-acquired pneumonia, 5 patients with meningitis, and 3 patients with pneumonia and meningitis) and 50 age-matched control subjects were included. The polymorphisms were determined by the polymerase chain reaction. In patients with pneumococcal disease, the lipopolysaccharide-stimulated tumor necrosis factor and interleukin-10 release from whole blood were measured by ELISA. Sepsis severity was documented according to standard criteria. No significant genotypic differences were seen between patients and control subjects. Thirteen of 69 patients with pneumococcal disease developed septic shock. Interleukin-10 allele G homozygous patients had the highest risk for septic shock (odds ratio of 6.1; 95% confidence interval, 1.4-27.2; corrected p = 0.024). The stimulated interleukin-10 release was highest in interleukin-10 G homozygous patients (p = 0.04). In conclusion, interleukin-10 polymorphism, associated with high interleukin-10 inducibility, might influence the outcome of pneumococcal infection via induced immunosuppression and impaired bacterial clearance.
Assuntos
Interleucina-10/genética , Meningite Pneumocócica/imunologia , Pneumonia Pneumocócica/imunologia , Polimorfismo Genético/genética , Regiões Promotoras Genéticas/genética , Choque Séptico/imunologia , Idoso , Alelos , Estudos de Casos e Controles , Infecções Comunitárias Adquiridas/imunologia , Intervalos de Confiança , Feminino , Genótipo , Homozigoto , Humanos , Interleucina-10/sangue , Linfotoxina-alfa/genética , Masculino , Meningite Pneumocócica/genética , Pessoa de Meia-Idade , Razão de Chances , Pneumonia Pneumocócica/genética , Estudos Prospectivos , Fatores de Risco , Choque Séptico/genética , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/genéticaRESUMO
Patients with hypereosinophilia frequently suffer from eosinophil-mediated damages of the heart, lungs, skin, and other organs, while some do not. The reason(s) for this difference is not known. We observed that eosinophils from most patients with hypereosinophilia express the alpha-chain of the IL-2 receptor (CD25), and that IL-2 enhances platelet-activating factor-stimulated release of eosinophil cationic protein from CD25-expressing but not from CD25-negative eosinophils. Such a "priming" effect has previously been described for eosinophil hematopoietins. These data suggest that patients with increased eosinophil surface CD25 expression are at higher risk of eosinophil degranulation and subsequent tissue damage when IL-2 is present at inflammatory sites.
Assuntos
Degranulação Celular , Eosinofilia/imunologia , Eosinófilos/imunologia , Interleucina-2/farmacologia , Ribonucleases , Asma/imunologia , Proteínas Sanguíneas/metabolismo , Dermatite Atópica/imunologia , Sinergismo Farmacológico , Proteínas Granulares de Eosinófilos , Eosinofilia/tratamento farmacológico , Eosinófilos/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Síndrome Hipereosinofílica/imunologia , Interleucina-5/farmacologia , Fator de Ativação de Plaquetas/farmacologia , Receptores de Interleucina-2/metabolismo , Receptores de Interleucina-2/fisiologia , SíndromeRESUMO
Although many membrane components have been described to be involved in the activation of cells by bacterial lipopolysaccharide (LPS), the question remains whether LPS, once internalized by target cells, is also capable of interacting with cytoplasmic elements in such a way that activation of cells results independently of receptor engagement. This is an important aspect to consider with respect to the development of strategies aimed at attenuating adverse effects of LPS in the framework of bacterial infections. In this study, human monocyte derived macrophages as representatives of one of the primary target cells activated by LPS, were microinjected with LPS to circumvent exogenous LPS stimulation. Parameters correlating to cytoplasmic activation of the nuclear transcription factor NFkappaB (intracellular calcium mobilization), to nuclear translocation of the NFkappaB p65 subunit and to mRNA-transcription of inflammatory cytokines known to be expressed upon exogenous LPS-stimulation and to require NFkappaB activation (interleukin-1beta, interleukin-6, tumor necrosis factor alpha) were investigated. In addition, the LPS-reporter cell line 3E10, which contains a reporter gene under the control of an NFkappaB-inducible promoter was analyzed with respect to NFkappaB nuclear translocation and reporter gene expression. None of the cellular systems used and none of the parameters investigated led to the observation that intracellular LPS leads to activation of the cells in comparison to external LPS stimulation. These experiments allow the conclusion that LPS in the cytoplasmic compartment does not lead to NFkappaB translocation, cytokine mRNA transcription, and NFkappaB dependent protein expression and suggest that these activation parameters require the interaction of LPS with external membrane components.
Assuntos
Infecções Bacterianas/metabolismo , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Inflamação/metabolismo , Lipopolissacarídeos/metabolismo , Macrófagos/metabolismo , NF-kappa B/metabolismo , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Transporte Ativo do Núcleo Celular/genética , Infecções Bacterianas/fisiopatologia , Cálcio/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Células Cultivadas , Citocinas/genética , Relação Dose-Resposta a Droga , Humanos , Inflamação/microbiologia , Inflamação/fisiopatologia , Interleucina-1/genética , Interleucina-6/genética , Líquido Intracelular/efeitos dos fármacos , Líquido Intracelular/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , NF-kappa B/efeitos dos fármacos , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Receptores de Interleucina-2/efeitos dos fármacos , Receptores de Interleucina-2/metabolismo , Fator de Necrose Tumoral alfa/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genéticaRESUMO
To elucidate whether the fraction of CD28(-) T cells within the CD4(+) T-cell population is a major source of Th1-like and proinflammatory cytokine production driving Wegener's granulomatosis (WG) granuloma formation, we analyzed the phenotype and functional characteristics of peripheral blood CD4(+)CD28(-) T cells and of T cells in granulomatous lesions of 12 patients with active WG. Surface markers and intracytoplasmic cytokine and perforin expression were assessed by flow cytometry. Cytokine secretion was measured by enzyme-linked immunosorbent assay. Immunohistological studies demonstrated interferon-gamma and tumor necrosis factor-alpha cytokine positivity attributable to CD4(+)CD28(-) T cells in granulomatous lesions. Peripheral blood CD4(+)CD28(-) T cells expressed CD57, also found on natural killer cells, and intracytoplasmic perforin. They were generally CD25 (interleukin-2 receptor)-negative. CD18 (adhesion molecule beta(2)-integrin) was strongly up-regulated on CD4(+)CD28(-) T cells, whereas only a minority of CD4(+)CD28(+) T cells expressed CD18. CD4(+)CD28(-) T cells appeared as a major source of interferon-gamma and tumor necrosis factor-alpha. In contrast, CD4(+)CD28(+) T cells were able to produce and secrete a wider variety of cytokines including interleukin-2. One-quarter of CD4(+)CD28(+) T cells expressed the activation marker CD25, but they lacked perforin. Thus, CD4(+)CD28(-) T cells appeared more differentiated than CD4(+)CD28(+) T cells. They displayed Th1-like cytokine production and features suggestive of the capability of CD4(+) T-cell-mediated cytotoxicity. CD4(+)CD28(-) T cells may be recruited into granulomatous lesions from the blood via CD18 interaction, and may subsequently promote monocyte accumulation and granuloma formation through their cytokine secretion in WG.
Assuntos
Granuloma/patologia , Granulomatose com Poliangiite/patologia , Interferon gama/metabolismo , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Antígenos CD28/análise , Antígenos CD4/análise , Citocinas/biossíntese , Citocinas/metabolismo , Citoplasma/metabolismo , Feminino , Citometria de Fluxo , Granulomatose com Poliangiite/metabolismo , Humanos , Imuno-Histoquímica , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Linfócitos T/imunologiaRESUMO
In sarcoidosis, host genetic factors are discussed as contributing to disease susceptibility and course. Since tumor necrosis factor (TNF)-alpha is a central mediator of granuloma formation and since elevated TNF-alpha levels are found during active phases of sarcoidosis, genetic polymorphisms correlating with influences on TNF-alpha levels are of special interest. The complete sequencing of the MHC region and the increase in the number of identified gene polymorphisms in this locus associated with TNF-alpha production offer the opportunity of detecting new genes associated with sarcoidosis and perhaps of defining disease-associated haplotypes that bear the potential of serving as predictive markers for this disease.